xcex1,xcex1-Dibromo-xcex1-chloro acetophenone compounds are reacted with nucleophiles to yield aromatic carbonyl compounds. In an important aspect, 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide is prepared by reacting 2,5-bis(2,2,2-trifluoroethoxy)-xcex1,xcex1-dibromo-xcex1-chloro acetophenone with 2-(2-aminomethyl)pyridine and reducing the piperidine ring.
2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide (III) is a known medicament useful for the treatment of arrhythmia and is described in U.S. Pat. No. 3,900,481. It is commercially available as its acetate salt. Methods for its synthesis are described, for example, in U.S. Pat. Nos. 4,642,384 and 4,617,396.
The synthetic method described in U.S. Pat. No. 4,642,384 involves the preparation of 2,5-bis(2,2,2-trifluoroethoxy)-.,a-dichloroacetophenone as an intermediate by chlorinating the a-unsubstituted 2,5-bis(2,2,2-trifluoroethoxy)acetophenone with chlorine gas at a moderate temperature, such as 50-60xc2x0 C. The xcex1,xcex1-dichloroacetophenone intermediate is further chlorinated in the presence of a buffering base, such as sodium acetate, at a slightly higher temperature, such as 80-100xc2x0 C. to yield the xcex1,xcex1,xcex1-trichloroacetophenone. The xcex1,xcex1,xcex1-trichloroacetophenone is reacted with 2-aminomethylpyridine to yield a benzamide, and the pyridine ring is reduced to yield 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide.
The inventive process is based on the discovery that the xcex1,xcex1-dibromo-xcex1-chloroacetophenone is easily prepared in high yield and purity under mild conditions, and that it is a superior leaving group in nucleophilic substitution reactions.
In one aspect this invention relates to a process for preparing the anti-arrhythmic agent, 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide (III), commonly known as flecainide, and pharmaceutically acceptable salts thereof, in particular the acetate salt.
The synthetic route comprises the reaction of 2,5-bis(2,2,2-trifluoroethoxy)-xcex1,xcex1-dibromo-xcex1-chloro acetophenone (I) with 2-(aminomethyl)pyridine to form the corresponding benzamide (II). The pyridyl ring of the benzamide (II) is then reduced to the piperidinyl moiety yielding the desired compound, flecainide acetate (III). The reaction scheme with preferred reagents is set forth below: 
Since the bulky dibromochloromethyl group is an excellent leaving group, (I) undergoes a facile amidization reaction with 2-aminomethylpyridine under mild conditions, such as at room temperature. It is preferred to carry out the reaction in an inert, non-polar solvent, such as toluene, hexane and the like, preferably a mixture of toluene and hexane. 
The reduction of pyridine rings to piperidine rings is well known and can be effected many means, such as hydrogenation, or reduction with a metal hydride, a metal or dithionite. Hydrogenation is carried out by contacting a solution of the benzamide (II) with hydrogen in the presence of a hydrogenation catalyst, such as Pt/C, Pt, Pt/PtO2 Pd/C, Rh/C, or Raney nickel. However, since it is unnecessary to protect any of the other functional groups in the molecule when the reduction is carried out by hydrogenation with a platinum-carbon catalyst, and since yields and purity are excellent, hydrogenation with a platinum-carbon catalyst is preferred.
Alternatively, for the preparation of flecainide, 2,5-bis(2,2,2-trifluoroethoxy)-Q,(xcex1, xcex1-dibromo-xcex1-chloro acetophenone (I) can be reacted directly with 2-aminomethylpiperidine, avoiding the reduction step. However, the formation of impurities makes the two step synthetic scheme described above preferable.
This invention further relates to the synthon 2,5-bis(2,2,2-trifluoroethoxy)-xcex1,xcex1-dibromo-xcex1-chloro acetophenone (I). The bulky dibromochloromethyl group is an excellent leaving group for nucleophilic substitution reactions.
2,5-bis(2,2,2-trifluoroethoxy)-xcex1,xcex1-dibromo-xcex1-chloro acetophenone (1) is preferably prepared from 2,5-bis(2,2,2-trifluoroethoxy)-xcex1-chloro-acetophenone by reaction with bromine, preferably under neutral or acidic conditions, such as in glacial acetic acid in the presence of sodium acetate. Alternatively, other bromination methods, such as reaction with an N-bromoamide like N-bromosuccinimide, are also useful. 
The 2,5-bis(2,2,2-trifluoroethoxy)-xcex1-chloro-acetophenone starting material is prepared by known methods. For example, a monochloro acetyl group is introduced to the ortho position of 1,4-bis(2,2,2-trifluoroethoxy)-benzene by a Friedel Crafts reaction using 2-chloroacetylchloride and a Lewis acid catalyst, such as tin chloride, ferric chloride or preferably, aluminum chloride, in the presence of a chlorinated hydrocarbon solvent, preferably methylene chloride. 
The 1,4-bis(2,2,2-trifluoroethoxy)-benzene in turn is prepared by reacting 1,4-dibromobenzene with sodium 2,2,2-trifluoroethoxylate in the presence of cupric bromide as described in U.S. Pat. Nos. 4,684,733 and 4,650,873, which are here incorporated by reference.
The present invention further relates to the use of an xcex1,xcex1-dibromo-xcex1-chloro acetophenone as a reagent in nucleophilic substitution reactions whereby the bulky dibromochloromethyl group is a leaving group that is replaced by a nucleophile, such as an amine, an alcohol, a mercaptan, an amide or a carbanion-forming compound. Particularly interesting carbanion forming compounds are carbonyl compounds having an xcex1-hydrogen atom, for example, ketones and esters having a methyl or methyene group adjacent to the carbonyl group, and Grignard reagents. Thus, the present invention includes a process for preparing an aromatic carbonyl compound, which comprises (a) preparing an xcex1,xcex1-dibromo-xcex1-chloro derivative of an acetophenone compound and (b) reacting the xcex1,xcex1-dibromo-xcex1-chloro derivative of the acetophenone compound with an amine, an alcohol, a mercaptan, an amide or a carbanion-forming compound.
The instance where the aromatic carbonyl compound is a benzamide is an important process of the present invention. Thus, the present invention further relates to a process for preparing a benzamide which comprises reacting an xcex1,xcex1-dibromo-xcex1-chloro acetophenone compound with a primary or secondary amine. 
The phenyl ring of the xcex1,xcex1-dibromo-xcex1-chloro acetophenone compound is unsubstituted or substituted by R1 and R2 substituents which are independently, for example, hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C6-alkoxy, xe2x80x94N(C1-C6-alkyl)2, xe2x80x94Sxe2x80x94C1-C6-alkyl, or phenyl; wherein the alkyl groups are unsubstituted or substituted by one or more halogen, hydroxy, xe2x80x94S-alkyl, xe2x80x94O-alkyl, carboxy, amido, or ester groups and when R1 or R2 is a phenyl substituent it is unsubstituted or substituted in the phenyl ring by halogen, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C6-alkoxy, xe2x80x94N(C1-C6-alkyl)2, or xe2x80x94Sxe2x80x94C1-C6-alkyl wherein the alkyl groups are unsubstituted or substituted by one or more halogen, hydroxy, xe2x80x94S-alkyl, xe2x80x94O-alkyl, carboxy, amido, or ester groups; or R1 and R2 together with the phenyl ring carbons to which they are attached form a 5-7 member aliphatic, aromatic, heterocyclic or heteroaromatic ring.
One embodiment includes those compounds wherein the phenyl ring of the xcex1,xcex1-dibromo-xcex1-chloro acetophenone compound is unsubstituted or substituted by R1 and R2 substituents which are independently hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, C1-C6-alkoxy, xe2x80x94N(C1-C6-alkyl)2, or xe2x80x94Sxe2x80x94C1-C6-alkyl; wherein the alkyl groups are unsubstituted or substituted by one or more halogen, hydroxy, xe2x80x94S-alkyl, xe2x80x94O-alkyl, carboxy, amido, or ester groups. An alternate embodiment include those compounds wherein R1 and R2 are independently hydrogen, C1-C4-alkyl, C3-C7-cycloalkyl, or C1-C4-alkoxy wherein the alkyl groups are unsubstituted or substituted by one or more halogen, hydroxy, or xe2x80x94O-alkyl substituents. Further alternate embodiments include those compounds wherein at least one of R1 and R2 is substituted or unsubstituted C1-C4-alkyl; substituted or unsubstituted C3-C7-cycloalkyl; substituted or unsubstituted C1-C4-alkoxy; substituted or unsubstituted xe2x80x94N(C1-C4-alkyl)2; or substituted or unsubstituted xe2x80x94Sxe2x80x94C1-C4-alkyl.
Preferably, R1 is in the 4-position when R2 is hydrogen, or R1 is in the 2-position and R2 is in the 5-position when R2 is other than hydrogen.
The nitrogen substituents, R3 and R4, are independently, for example, hydrogen or unsubstituted C1-C6-alkyl or C1-C6-alkyl which is substituted by one or more of, for example, xe2x80x94OH, halogen, alkoxy, or an aliphatic, aromatic, heterocyclic or heteroaromatic ring; or R3 and R4 together with the nitrogen atom form a heterocyclic ring such as a piperidine, piperazine, pyrrole, or morpholine ring.
Examples of suitable xcex1,xcex1-dibromo-xcex1-chloro acetophenone compounds include 2-hydroxy-5-chloro-xcex1,xcex1-dibromo-xcex1-chloro acetophenone which is reacted with 2-chloro-4-nitro-aniline to yield the therapeutic agent niclosamide.
The present invention further relates to xcex1,xcex1-dibromo-xcex1-chlorophenone compounds of the formula 
wherein R1 and R2, and the embodiments thereof, are described above. The compounds are useful as intermediates for the preparation of aromatic carbonyl compounds.
The following examples are intended to illustrate, but not limit, the inventive process.